CN100536912C - Use of HCG in controlled ovarian hyperstimulation - Google Patents
Use of HCG in controlled ovarian hyperstimulation Download PDFInfo
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- CN100536912C CN100536912C CNB028175735A CN02817573A CN100536912C CN 100536912 C CN100536912 C CN 100536912C CN B028175735 A CNB028175735 A CN B028175735A CN 02817573 A CN02817573 A CN 02817573A CN 100536912 C CN100536912 C CN 100536912C
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/22—Hormones
- A61K38/24—Follicle-stimulating hormone [FSH]; Chorionic gonadotropins, e.g. HCG; Luteinising hormone [LH]; Thyroid-stimulating hormone [TSH]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/06—Antiabortive agents; Labour repressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Reproductive Health (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pregnancy & Childbirth (AREA)
- Gynecology & Obstetrics (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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- Medicinal Preparation (AREA)
Abstract
The invention provides a protocol leading to improved embryo implantation rates and/or decreased miscarriage rates in which hCG, or a bio-analogue, is administered during the follicular phase.
Description
Technical field
The present invention relates to inside and outside auxiliary procreation technology (ART) field, particularly use promoting sexual gland hormone controlled super ovulation (controlled ovarian hyperstimulation, COH).
Background of invention
Adopt auxiliary procreation technology, for example external fertilization (IVF) or IVF combine with intracytoplasmic sperm injection (ICSI) in the ovum endochylema and embryo transfer (ET) treatment infertility, need COH to increase the quantity of women's gamete
(1)The standard scheme of COH
(2)Comprise a stage of regulating downwards, in this stage, suppress endogenous luteotropic hormone (LH) by giving gonadotropin releasing hormone (GnRH) agonist, what follow is a stimulation period, in this stage, give follicule-stimulating hormone (FSH) (FSH) every day, about usually 150IU/ days, induce follicular development (follicle generation).Active other molecules of FSH also can have been adopted.Another kind of select be calendar month through or induce menstruation after begin to stimulate, began at about the 6th or 7 day that gives FSH usually, prevent the LH peak by giving the GnRH antagonist.In the super ovulation scheme of teaching reproductive technology, main purpose is to obtain many follicular developments.When having 3 follicles at least〉when 16 millimeters (one of them is 18 millimeters), (5-10 000IU) causes ovulation to give single pill (single bolus) hCG.Be decided to be the time of reclaiming oocyte in 36-38 hour behind the injection hCG.
It is to prevent from immaturity ovulation and the luteinic LH of follicle peak to occur causing in the unsuitable time that the present invention uses the ultimate principle of GnRH agonist and antagonist
(3)Widespread usage has been clinically for the GnRH agonist therapy.Have found that, long-time therapeutic scheme (promptly the midluteal phase in cycle begin earlier induced ovulation or before the scheme of beginning) arrange administration time, higher, the clinical whole result of follicle productive rate better easilier to the patient
(4)Adopt the GnRH antagonist relatively novel clinically, but estimate to obtain similar beneficial effect, also have the shorter advantage of treatment cycle.
Prolong the time that gives the GnRH agonist or give the GnRH antagonist, endogenous LH can be suppressed greatly.This different with free period with the conflicting situation of follicular development.The LH level of free period slowly increases progressively, and peaks in mid-term after several days.
Someone has probed into the effect of chorionic-gonadotropin hormone (CG) in induced ovulation and auxiliary procreation technology.Generally acknowledge in well-known and present technique field: the technology of induced ovulation and method and COH scheme are completely different, give FSH although the two all may relate to.
People such as Filicori have studied succedaneum the effect in controlled super ovulation of low dosage hCG as LH
(5)The giving of the giving of hCG (50IU hCG/ days) and FSH begins simultaneously, gives hCG continuously every day, until causing ovulation with the hCG pill.Accept the group of hCG and only accept 14 millimeters of the resulting little follicle of group (＜10 millimeters) of FSH, middle follicle (10-14 millimeter) and large follicles (〉) quantity is approaching, but the integral dose of the FSH of hCG treatment group and the stimulation time of FSH all reduce.
People such as Messinis have reported no ovum women's (WHO group I) induced ovulation, and the therapy of employing is to give daily dose hMG (each 75IU of FSH and LH) in stimulation period, gives single dose or multiple dose hCG in luteal phase.Found that patient's pregnancy rate of accepting multiple dose hCG in luteal phase induces/causes the matched group of the single dose hCG of ovulating that remarkable rising is arranged than only accepting
(6)
Certainly, suitable follicular development is the primary condition that the auxiliary procreation technology method is succeedd.Yet, have ovulation of some situations and fertilization all to finish, but embryo's inappropriate implantation cause can't be conceived.Other situations are the junior three of pregnancy month natural premature labors (miscarriage).These two problems are all relevant with endometrial situation, and endometrium is quite responsive to hormonal readiness.
This shows,, but still do not guarantee successful pregnancy, because often run into implantation and premature labor problem even follicular development, ovulation and fertilization have all taken place.
Some patients easily miscarriage or problem that can't implantation can be resolved at last, need repeat a plurality of ART cycles but do like this, and the result produces negative effect to patient's physiology and psychology.For other patients, these problems are to make the permanent obstacle that they can not be conceived.
Therefore, be necessary to provide and improve implantation rate and reduce productive rate early, particularly with the bonded method of COH.
Summary of the invention
One object of the present invention is to provide a kind of promoting sexual gland hormone that gives to carry out COH, thereby improves implantation rate and reduce improving one's methods of abortion ratio.
Another object of the present invention be to provide a kind of for example by improve implantation rate and/or reduce abortion ratio so that do not carry out COH the patient such as spontaneous ovulation week after date patient or the patient that the accepts induced ovulation method that increases pregnancy rate.
A first aspect of the present invention is to provide human chorionic gonadotropin (hCG) or the application of its analog in the medicine of preparation promotion people patient's embryo nidation and/or reduction embryo abortion ratio, and described medicine gives in ovulation or before causing ovulation.
A second aspect of the present invention is to provide hCG or the application of its analog in promoting people patient's embryo nidation and/or reduction embryo abortion ratio, and described hCG or its analog give in ovulation or before causing ovulation.
A third aspect of the present invention is to provide hCG or its analog to use for the people patient who adopts FSH or its analog in conjunction with controlled super ovulation (COH) in preparation, with the application in the medicine of auxiliary implantation and/or reduction abortion ratio, described medicine began to give before the 10th day after beginning FSH treatment.
A fourth aspect of the present invention is to provide hCG or its analog using for the people patient who adopts FSH or its analog in conjunction with COH, with the application in auxiliary implantation and/or the reduction abortion ratio, described hCG or its analog began to give before the 10th day after beginning FSH treatment.
A fifth aspect of the present invention is to provide a kind of pharmaceutical composition, and it is used for auxiliary embryo nidation and/or reduces abortion ratio, randomly preferably combines with COH, and the every dosage of described pharmaceutical composition contains 25-1000IU hCG or its analog.
Another aspect of the present invention is to provide the people patient's usefulness for employing FSH or its analog in conjunction with COH, and with hCG or its analog of auxiliary implantation and/or reduction abortion ratio, described hCG or its analog began to give before the 10th day after beginning FSH treatment.
In another embodiment, the invention provides the hCG or its analog that promote people patient's embryo nidation and/or reduce embryo's abortion ratio, described hCG or its analog give in ovulation or before causing ovulation.
The method that another aspect of the present invention is to provide a kind of people of promotion patient implantation and/or reduces abortion ratio, described method combines with the COH that adopts FSH or its analog, described method comprises and gives the patient hCG or its analog that wherein said giving began before the 10th day after beginning FSH treatment.
The present invention also provides a kind of patient's of promotion implantation and/or reduces the method for abortion ratio, and described method comprises and give the patient hCG or its analog, and wherein said hCG or its analog are in ovulation or cause and give before ovulating.
Another aspect of the present invention is to provide the test kit of a kind of COH of being used for, this test kit contain every day 12 or more than, best 14 or above dose F SH, preferred about 75-200IU FSH/ days, be more preferably about 150IU FSH/ days, and every day 4-8,5-8 or 6-8 dosage hCG, for example, every day 4,5,6,7 or 8 dosage hCG preferably about 25-1000IU hCG/ days, are more preferably about 50-100IU hCG/ days.
The test kit that a kind of auxiliary embryo nidation is provided on the one hand again and/or reduces abortion ratio of the present invention, this test kit contains 4-8 every day, 5-8 or 6-8 dosage hCG, for example, and every day 4,5,6,7 or 8 dosage hCG, about 25-1000IU hCG/ days, preferably about 50-100IU hCG/ days.These test kits can or needn't with the COH coupling.
Test kit of the present invention becomes to be used in use in method of the present invention and the application with the pharmaceutical composition preferred design.
The specific embodiment
Human chorionic gonadotropin (hCG) is a kind of heterodimer glycated peptide hormone that is produced by Placenta Hominis at phenolics.It occurs after fertilization in serum very soon, plays a part to keep corpus luteum after the LH secretion reduces, to support estrogen and progesterone continuous release and to prevent in the period.Because it only is present among the pregnant woman with high level, play an important role in the cycle so it can not be regarded as spontaneous ovulation.As everyone knows, the receptor of hCG is present in gonad, uterus, fallopian tube, Placenta Hominis and endometrial cell and the myometrium cell
(7)The half-life of hCG is the longest in promoting sexual gland hormone
(8)
The inventor is surprised to find that, gives low dosage hCG or analog in the stimulation period in ART cycle, for example by auxiliary or improve implantation and/or reduce abortion ratio and pregnancy rate is had useful effect.Term " low dosage " is included in the particular patient, is the dosage that the last used dosage (" follicle (or ovulation) amount of initiator ") of follicle maturity lacks than generally being used for causing follicle maturity before ovulation.The follicle of hCG/ovulation amount of initiator (generally 5,000 to 10, in the 000IU hCG scope) changes with each patient.
From above about the discussion of standard C OH therapeutic scheme as can be known, the hCG that is somebody's turn to do " high dose " or ovulation amount of initiator causes step, oocyte maturation step or ovulation stimulation step being commonly referred to ovulation in the art.Yet such ovulation that gives high dose hCG stimulates or causes step or oocyte maturation step only in COH scheme stimulation period, promptly has enough follicular developments just can carry out in the stage of inducing follicle and generating giving FSH or its analog.Methods and applications of the present invention are compared with the therapeutic scheme of prior art, give hCG before main difference is promptly to have before enough follicular developments and generation is ovulated or initiation is ovulated in stimulation period, and the dosage that gives is lower than the dosage of inducing oocyte maturation and induction of ovulation, promptly is lower than the ovulation amount of initiator.This therapy of the present invention has obvious advantage aspect implantation and the miscarriage.So, according to the present invention, before enough follicular developments are arranged and the high dose hCG that causes ovulation at last to cause before oocyte maturation and the ovulation, in stimulation period, give low dosage hCG, and combine with the COH scheme.
Of the present invention aspect these in, if the patient does not carry out COH, also can be in the follicle generation phase and reached enough follicular development before give low dosage hCG.These dosage of hCG are lower than the ovulation amount of initiator.As mentioned above, these patients have a spontaneous ovulation cycle, at this moment, and the hCG of the amount of initiator of needn't ovulating at last.Yet, but some do not carry out COH and the method according to this invention and give the patient that low dosage hCG treats and (for example may not have the spontaneous ovulation cycle, those carry out the patient of induced ovulation), in the case, judge the hCG of the amount of initiator of can ovulating after the follicular development reach enough.
When in various situations of the present invention, using hCG, used dosage should be in 25-4000IU hCG/ days scope, preferably in 25-1000IU hCG/ days scope, be more preferably in the scope of 30-1000 or 30-500IU hCG/ days, be preferably in 50-100IU or 75-125IU hCG/ days or 75-100IU hCG/ days or 75 or 100 to 500 or 75 or 100 to 1000IU hCG/ days scope.These dosage all are lower than the ovulation amount of initiator, and as mentioned above, this paper is called them " low dosage " hCG.If use the hCG analog, should be equivalent to the dose,equivalent of these hCG dosage.
As mentioned above, the present invention also provides and can contain in method of the present invention and pharmaceutical composition or the test kit of the hCG of the above-mentioned dosage of using in using.
Of the present invention aspect these in, if hCG (or its analog) and the COH coupling of adopting FSH or its analog, hCG (or its analog) should be after beginning FSH treatment before the 10th day, is more preferably after beginning FSH treats to begin to give before the 9th day.HCG preferably after beginning FSH treatment at least 3 talentes begin to give, for example after beginning FSH treatment between the 3rd day to the 10th day, be more preferably begin FSH treat after at least 5 or 6 talentes begin to give.HCG preferably should be after beginning FSH treatment the 7th or 8 day or the about the 7th or 8 talentes begin to give.So, in follicular phase, giving hCG, the preferred time point that gives hCG is in the follicle mid-term in cycle or at the follicle surrounding time in mid-term, promptly begins the FSH treatment at least 5,6,7 or 8 days afterwards.
According to the present invention, giving of hCG can be single pill, in the case, it preferably should give at the 7th or 8 day or about the 7th or 8 day after beginning FSH treatment, and dosage preferably should contain 100-1000IU hCG, be more preferably and contain 100-500IU hCG or 150-600IU hCG, preferably contain the 250IU hCG that has an appointment.Give medical personnel and patient all very convenient with single pill.
On the other hand, according to the present invention, can give hCG every day until causing follicle maturity or induce/cause ovulation with common hCG pill.For giving every day, dosage should be in 25-4000IU hCG/ days scope, preferably in 25-1000IU hCG/ days scope, be more preferably in the scope of 30-1000 or 30-500IU hCG/ days, be preferably in 50-100IU or 75-125IU hCG/ days or at 75-100 or 75 or 100 to 500 or 75 or 100 to 1000IU hCG/ days scope.Have found that scheme every day of beginning in the 7th day and hCG/ days dosage of employing 50-100IU is effective especially after beginning FSH treatment.The number of times that gives hCG also can reduce, and for example per 2 days, per 3 days or per 4 days, gives hCG in preferred per 2 days, until causing ovulation.In these schemes, also available above-mentioned those dosage of listing are though preferred dose of the present invention is 50-200IUhCG.
Clearly visible from above discussion, the used hCG of the present invention is giving before ovulating or before for example causing ovulation with the hCG of ovulation amount of initiator, and continues to and ovulation takes place or cause ovulation.In whole schemes of the present invention, if think favourable to the patient, having needs, and can continue to give hCG after ovulation.
The time that gives the hCG of " follicle/ovulation amount of initiator " and cause ovulation, the technical staff for ART scheme field was known, also was confirmable.Usually, when thinking that follicular development is enough to selected the sort of scheme, just cause ovulation.The follicular development level is generally by measuring follicle size (for example using ultrasound wave) and patient's serum estradiol (E
2) level determines.If described scheme is COH, so because the purpose of these methods is many follicular developments, produce incremental number purpose mature follicle/oocyte, they are generally at external fertilization, replant in patient's body, so if causing the time of ovulation may be that time of induced ovulation is slightly different with described scheme, in the induced ovulation scheme, its objective is to produce 1 or maximum 2 mature follicles, they are ovulated in vivo and are fertilized.For example, in the embodiment of relevant COH scheme, when detecting the diameter 18mm that has 2 follicles at least, and the serum estradiol level is when reaching 300pg/ml, and is available 5,000 to 10,000, and for example 10,000IU hCG causes ovulation.Another selection is in the embodiment of relevant COH scheme, when the average diameter of maximum follicle reaches 18mm at least, has the average diameter 16mm (i.e. at least 3 follicle 16mm, one of them 18mm) of other 2 follicles at least, simultaneously for the follicle number that exists, estradiol (E
2) level when (about 150pg/ml/ mature follicle), can cause ovulation within acceptable scope.For induced ovulation, when having 1 follicle 17mm at least, the hCG of the amount of initiator of can ovulating (, just needn't give) if surpass 3 equal 15mm of follicle.
The hCG half-life in vivo is longer relatively.Therefore, must be noted that when with multiple dose integral dose can not arrive nonconforming high level.Preferred serum hCG level was not higher than 50IU/L basically before giving the induced ovulation pill, be more preferably not to be higher than 25IU/L, preferably was not higher than about 10IU/L.If the hCG level is higher than this level basically, the possibility of result causes the immaturity luteinization.People such as Mannaerts have reported the pharmacokinetics of single dose intravenous injection hCG after intramuscular and subcutaneous injection
(9)
In the present invention in the situation of FSH (or analog) and COH technology or scheme coupling, proper dosage and give scheme and will be apparent to those skilled in the art can be used any proper dosage and give scheme.For example, but FSH give every day, the dosage that gives is or about 75 to 250 or 75 to 200IU/ days, preferably or about 150 to 200/ days, preferably or about 150IU/ days.Some patients are relatively poor to replying of FSH, the highest the most handy 600IU/ days daily dose.A typical scenario is such: the patient began with 150IU FSH/ days, carried out ultrasound wave assessment follicular development after 3 or 4 days.If follicular development is enough, can keep 150IU FSH/ days dosage.If follicular development is inadequate, dosage can be increased to 225,300,375,450,525 or 600IU FSH/ days.Preferably continue to give FSH, until the hCG of the amount of initiator of ovulating.Ideal situation is that the integral dose of FSH should not surpass the 6000IU/ cycle.
This paper for example comprises when comparing with one or more untreated patients' implantation or pregnant level or incidence rate about the used term of implantation and pregnancy effect " raising rate ", " promotion ", " assisting ", " increment rate " or the like, perhaps when comparing in early time point (for example comparing with " benchmark " level) viewed implantation or pregnant level or incidence rate with same patient, maybe this group patient's implantation or pregnant incidence rate have any improvement that measures or raising to accept this individuality of the inventive method treatment.For example, in the embodiment of hCG and COH coupling, correlation ratio is to make comparisons to this group patient of the patient of the method treatment of accepting these embodiment and the conventional COH treatment of acceptance or with the same patient who accepts conventional COH treatment.This improvement or raising preferably have statistical significance, and the P value is preferably less than 0.05.The method that mensuration has a result of statistical significance has been behaved known, and the present technique field is on the books, can adopt any suitable method.
This paper refers to for example when comparing with one or more untreated patients' miscarriage incidence rate about the used term of abortion effect " reduction ", " minimizing " etc., perhaps when comparing in the viewed miscarriage incidence rate of time point (for example comparing with " benchmark " level) early with same patient, this individuality of accepting the inventive method treatment maybe this group patient's miscarriage incidence rate has any reduction that measures or minimizing.For example, in the embodiment of hCG and COH coupling, correlation ratio is to make comparisons to this group patient of the patient of the method treatment of accepting these embodiment and the conventional COH treatment of acceptance or with the same patient who accepts conventional COH treatment.This reduction preferably has statistical significance, and the P value is preferably less than 0.05.Most preferably, application of the present invention and method can prevention of miscarriage.So these terms also comprise prevention of miscarriage.
HCG of the present invention use can be used for being considered to its infertile may be because premature labor or can't implantation due to any patient on, no matter and whether this patient has and is accepting other exogenous promoting sexual gland hormone.
Miscarriage is defined as fetus to have and gives birth to before the independent survival capacity.Premature labor refers to those miscarriages in the initial generation in 1 middle of the month of fetal development.Methods and applications of the present invention are particularly useful to reducing the premature labor level.
HCG application of the present invention combines meeting and the coupling of external fertilization technology usually with COH.But, hCG as herein described use combine with COH also can with the internal fertilization coupling.
In addition, hCG of the present invention uses also can combine with internal fertilization and is used among the patient who does not carry out COH, for example, comprises spontaneous ovulation and for example with the scheme (promptly not giving the scheme of exogenous promoting sexual gland hormone) of estrogen antagonist or aromatase inhibitor induced ovulation.Do not accept when being used in ... in the time of among the patient of exogenous promoting sexual gland hormone, hCG begins to give before should estimating to ovulate in any one period demand, is preferably in menstruation and begins to give in the 6th, 7 or 8 day or about the 6th, 7 or 8 day afterwards.It is (for example above-mentioned about giving single pill described dosage to give single pill, 100-500IU hCG particularly), but perhaps give every day (for example above-mentioned about giving described dosage every day, 50-100IU hCG particularly), gave (for example above-mentioned dosage in perhaps per 2 days, 50-200IU hCG particularly), until spontaneous ovulation or cause ovulation with the hCG of above-mentioned ovulation amount of initiator whenever necessary.
Be used for not carrying out the patient's of COH the embodiment of the invention at hCG, these patients selectively use exogenous promoting sexual gland hormone (for example exogenous FSH) to carry out induced ovulation.Used suitable hCG dosage is as described in this paper context.As mentioned above, in due course between point cause ovulation with high dose hCG.
Like this, as implied above, will recognize that hCG of the present invention uses and combines with the COH scheme that adopts FSH is favourable, hCG also can be used to improve and does not carry out the COH scheme, but hope improves the people patient's of the chance of successfully becoming pregnant embryo nidation rate and/or reduction abortion ratio.These patients (or their spouse) have some fertility Issues usually, and are promptly infertile or fertility is low.In addition, also may there be obviously fertility Issue such as ovulation and fertilization etc. in the patient, but because easy premature labor and/or can't cause sterile by implantation.The women for example surpassed 35 years old women and generally had implantation and the high problem of abortion ratio advanced age, and they also are fit to treat with this method very much.
These patients can spontaneous ovulation, perhaps available induced ovulation scheme is carried out induced ovulation and without the COH scheme, for example, use (aromatase inhibitor stimulation of endogenous FSH secretions) such as aromatase inhibitors, perhaps discussed above give exogenous FSH the induced ovulation scheme.Some induced ovulation schemes all are the standard schemes of this area like this, existing complete narration.
In the application of not adopting the COH scheme, generally begin to calculate the time that gives hCG from menstruation that day, though in the induced ovulation scheme that adopts FSH, the time that gives can calculate from beginning FSH treatment that day.After the menstruation or the appropriate time after the beginning FSH treatment referring to above-mentioned discussion.As mentioned above, hCG begins to give in follicular phase ovulation (can be spontaneous ovulation or cause with the hCG of ovulation amount of initiator to ovulate) before, ovulate before the preferably ovulation mid-term in cycle the onset of ovulation, for example after the menstruation 5 to 8 days, for example after the menstruation the 6th, 7 or 8 day, perhaps begin the FSH treatment at least 5 or 6 days afterwards, for example began the FSH treatment 5,6,7 or 8 days afterwards.This shows that although these patients' therapeutic scheme adopts the patient of COH scheme of FSH different with those, the preferred time that gives hCG is similar, promptly at the surrounding time in ovulation mid-term in cycle or ovulation mid-term.
According to the present invention, giving hCG is useful to those patients that just accepting GnRH agonist or antagonist for treating.According to the present invention, hCG gives to combine particularly useful with IVF or IVF/ICSI.This method can improve implantation rate and initial 3 months pregnancy rate has been crossed in pregnancy.Use hCG even can help and be diagnosed as the patient's implantation that causes to carry out the IVF scheme owing to non-ovulation problem before some.
HCG of the present invention uses treating the patient of low endogenous LH levels, and the patient is particularly useful as hypogonadotropic hypogonadism.
HCG application of the present invention also can be used on those and for example only can't conceived maybe can't keep among the patient of pregnancy with FSH in standard C OH or induced ovulation scheme in the past.
Other patients that are suitable for for example are those polycystic ovary disease (PCOD) patients, luteal phase and the insufficient patient of immune factor and 35 years old and above patient (" advanced age " patient).Patient's age preferably is no more than 45 years old, is more preferably to be no more than 42 years old.
Used hCG can obtain from any resource, as long as the material (especially other promoting sexual gland hormone) that it is not subjected to any its effect of meeting appreciable impact pollutes.Though preferably used also available urine hCG because the purity of reorganization hCG (rhCG) is high.
The hCG analog comprises having the physiology identical with hCG, biochemistry or biological agent, and/or with the bonded whole molecules of the same receptor of hCG.As everyone knows, luteotropic hormone (LH) has some identical physiological actions with hCG, but for the purposes of this invention, the hCG analog does not comprise LH.
Some comprises single chain hCG in the hCG analog, wherein the N-terminal of the C-terminal of β-subunit and α-subunit merge (people such as Sugahara, PNAS, 92,1995,2041-2045).The example of other analog that have been disclosed can be referring to European patent EP 0322226 (Applied Research System), WO 92/22568 ((the University of Medicine ﹠amp of New Jersey's medical science and dentistry university; Dentistry of New Jersey)), WO96/05224 (University of Washington), WO 90/09800 (University of Washington), WO 93/06844 (University of Washington), WO 98/43999 (University of Washington), WO 99/25849 (University of Washington).
HCG can detect with any suitable technique, for example people such as Vaitukaitis
(10)Described radioimmunoassay detection method and ELISA test
(11)The biological activity of hCG can be measured with any suitable technique, for example mice Leydig cell bioassay method (Leydig cell bioassay)
(12)
In the embodiment of the invention that adopts FSH, those skilled in the art will recognize that FSH can replace by bioactive analogue, perhaps replace with the excretory chemical compound of stimulation of endogenous FSH.Latter event comprises aromatase inhibitor and estrogen antagonist such as tamoxifen (tamoxifen) and clomiphene citrate (CC).These chemical compounds are applied to hypothalamic negative feedback (perhaps by the antagonism estrogen receptor by eliminating estrogen, effect is the same with CC and tamoxifen, perhaps, act on the same with aromatase inhibitor by reducing estrogen concentrations greatly) come stimulation of endogenous FSH to secrete.
The preferred form that FSH and hCG of the present invention use coupling is called FSH-CTP.This long lasting people FSH describes in WO 93/06844, it has a wild type FSH α-subunit and a β-subunit, and this β-subunit is made up of the wild type FSH β-subunit that merges with the carboxyl terminal peptide (CTP) of hCG β-subunit (natural hCG β sequence residue post-11.2-118 to the position 145) on its carboxyl terminal.The FSH analog of other kinds comprises for example strand FSH analog, and wherein the CTP of β-subunit and hCG merges, and it merges with FSH α-subunit again, as (strand FSH-CTP) as described in the WO96/05224.
About as described in the hCG, the used FSH of the inventive method can obtain from any resource as above.These resources are that induced ovulation and COH program those skilled in the art are known.Available FSH urine preparation, for example the ratio of FSH and LH activity is the hMG of 1:1.Because the purity height of Recombinant FSH (rFSH), so preferably use rFSH.
In the stimulation period of the induced ovulation of IVF and COH, replaced FSH with human menopausal gonadotropin (hMG).HMG extracts in women's urine after menopause and the relative thicker hormone extract that obtains, and it has FSH and LH activity (1:1).Non-exclusive hM6 may contain few to 2% active hormones, therefore, may be the urine pollutant up to 98% protein content.When method of the present invention is selected hMG for use and during without FSH, as mentioned above, additional hCG has also proved and has helped such as auxiliary implantation and/or prevention or reduce miscarriage.HCG should begin to give before the 10th day after beginning hMG treatment, was more preferably after beginning hMG treatment to begin to give before the 9th day preferably beginning before the 7th or 8 day or about the 7th or 8 day after beginning hMG treatment.HCG just begins to give after 3 days after being preferably in beginning hMG treatment.Dosage and dosage regimen are with reference to the dosage and the dosage regimen of hCG and FSH coupling.Preferred dose is 150IU/ days, is more preferably 50 or 100IU hCG/ days.
Now, the present invention will be further described with following non-restrictive example.
Embodiment
Stimulation protocol
Matched group 1: menstruation the 1st day, inject triptorelin (decapeptyl) (0.1 milligram) desensitization every day for the patient.After 14 days, carry out sonography, do not have cyst, begin to stimulate with rFSH (150 to 200IU/ days).After 7 days,, and measure E by the sonography ovarian follicular growth
2Blood concentration.Every day the patient is checked, when detecting the diameter 18mm that has 2 follicles at least, while serum E
2Level when reaching 300pg/mL, with 10,000IU hCG causes ovulation.
Matched group 2: at the 7th day of matched group 1, matched group 2 was also accepted hMG (150IU/ days) except accepting rFSH.
Experimental group: at the 7th day of matched group, experimental group was accepted 50-100IU hCG every day, and gives and close rFSH, until causing ovulation as stated above.
Oocyte is at external fertilization.After 4 hours, they are cleaned, place culture fluid (ISM1).After 20 hours, check fertilization, make the embryo in same culture fluid, be cultured to 48 hours.Then, they are transferred in second kind of culture fluid (ISM2).Take out 2 best embryo transfers again in patient's body, continue to cultivate up to blastocyst formation (5-6 days).
The result
Experimental result is listed in table 1, table 2 and the table 3.Table 1 and table 2 are depicted as the comparative result of matched group 1 (only giving rFSH) and experimental group (giving rFSH+hCG).Table 3 is depicted as the comparative result of matched group 2 (giving rFSH+hMG) and experimental group (giving rFSH+hCG).
Time used in stimulation period does not have difference.Accept the experimental group E of hCG
2Level rises.Two groups implantation rate difference is little: accept hCG:92%, matched group: 86%, (p=0.1).That two groups of blastocysts that obtain from the supernumerary embryo tire form is almost equal (accept hCG:185/411=45%, matched group: 292/627=46.5%, p=0.622).The implantation rate of hCG group (accept hCG:24.5%, matched group: 14.6%, p=0.0134) with pregnancy rate (accept hCG:37.5%, matched group: 23.6%, p=0.0246) increase, transplant average 1.9 embryos at every turn.
Table 1: stimulation period is used the low dosage hCG experimental result of rFSH
| HCG is arranged | No hCG | |
| Patient's number | 96 | 127 |
| Grade (year) | 2.2(32.8±4.1) | 1.5(32.1±4.5)(p＝0.1068) |
| Transplant | 89(92％) | 109(86％) |
| Stimulation time (my god) | 11.7 | 12.3 |
| The oocyte that reclaims | 10 | 9.7 |
| Embryo (m) | 6.2(62％) | 5.4(56％) |
| Implantation | 43/175(24.5％) | 30/206(14.6％)(p＝0.0134) |
| Embryo/transplanting | 1.97 | 1.89 |
| Gestation | 36/96(37.5％) | 30/127(23.6％)(p＝0.0246) |
| Blastocyst | 185/411(45％) | 292/627(46.5％)(p＝0.6221) |
Table 2: stimulation period is used the low dosage hCG experimental result of rFSH
| HCG is arranged | No hCG | Add up to | |
| Gestation | 109 | 230 | 339 |
| Dystopy | 2 | 6 | 8(2.4％)(p＝0.95) |
| Miscarriage | 8(7.3％) | 36(15.6％) | 44(13％)(p＝0.03) |
| Miscarriage+dystopy sum | 10(9，17) | 42(18.3) | 52(15.7)(p＝0.03) |
Table 3: stimulation period is used low dosage hCG and the hMG experimental result of rFSH
| FSH+hCG | hMG | |
| Gestation | 109 | 76 |
| Dystopy | 2 | 2 |
| Miscarriage | 8 | 13(p＝0.049) |
| Miscarriage+dystopy sum | 10 | 15(p＝0.049) |
List of references
1.Healy etc.; Lancet 343 1994; 1539-1544.
2. the routine techniques of for example describing among the EP 0 170 502 (Serono laboratory company limited).
3.Filicori，M.；J.Clin.Endocrinol.Metab.81?1996；2413-6。
4.Filicori, M. etc.; Fertil.Steril.65 1996; 387-93.
5.Filicori etc.; J.Clin.Endocrinol.Metab.84 1999; 2659-2663.
6.Messinis?et?la.；Fertility?&?Sterility?50?1988；31-35。
7.Lei etc.; J.Clin.Endocrinol.Metab.75 1992; 651-659.
8.Bennett etc.; Pharmacol.Rev.30 1979; 247-292.
9.Mannaerts etc.; Human Reproduction 13 1998; 1461-1464.
10.Vaitukaitis etc.; Am.J.Obstet.Gynecol.113 1972; 751; Clin.Chem.311985; 1749.
11.Tyrey etc.; Obstet.Gynecol.Clin.North Am.15 1988; 457.
12.Robertson, W.R. and Binden, S.P; The vitro bioassay of peptide hormone (The in vitrobioassay of peptide hormones) .In Hutton, J.C. and Siddle, K. (volume), practice progress (the Peptide Hormones of peptide hormone; A Practical Approach) .IRL publishing house, Oxford (1990).
Claims (19)
1. human chorionic gonadotropin (hCG) is used for the people patient who adopts FSH or its analog in preparation, with the application in the medicine of auxiliary implantation in the controlled superovulated patient of experience, described medicine began to give before the 10th day after beginning FSH treatment, and described FSH analog is FSH-CTP.
2. application as claimed in claim 1 is characterized in that, described medicine began to give before the 9th day after beginning FSH treatment.
3. application as claimed in claim 1 or 2 is characterized in that, described medicine at least 3 talentes after beginning FSH treatment give.
4. application as claimed in claim 1 is characterized in that, described medicine began to give after beginning FSH treatment on the the 7th or 8 day.
5. application as claimed in claim 1 is characterized in that, described medicine gives with 25-1000IU hCG/ days dosage.
6. application as claimed in claim 1 is characterized in that, described medicine gives with 50-100IU hCG/ days dosage.
7. application as claimed in claim 1 is characterized in that described medicine gives with single pill.
8. application as claimed in claim 7 is characterized in that, described single pill gave after beginning FSH treatment on the the 7th or 8 day, and this pill contains 100-500IU hCG.
9. application as claimed in claim 1 is characterized in that, described medicine gives every day, until induced ovulation.
10. application as claimed in claim 1 is characterized in that, COH combines with external fertilization or internal fertilization and carries out.
11. application as claimed in claim 1 is characterized in that, the patient has the low shortcoming of endogenous luteotropic hormone (LH) level.
12. application as claimed in claim 1 is characterized in that, the patient only used follicule-stimulating hormone (FSH) (FSH) pregnancy maybe can't keep conceived in the past.
13. application as claimed in claim 1 is characterized in that, described hCG is reorganization hCG.
14. application as claimed in claim 1 is characterized in that, described hCG is urine hCG.
15. the application of human chorionic gonadotropin in the medicine of preparation promotion people patient embryo nidation, described medicine gives in ovulation or before causing ovulation.
16. application as claimed in claim 15 is characterized in that, described medicine gave with single pill after menstruation on the the 7th or 8 day.
17. application as claimed in claim 15 is characterized in that, the beginning in the 7th or 8 day after menstruation of described medicine gives every day, until ovulating.
18. application as claimed in claim 15 is characterized in that, described hCG is reorganization hCG or urine hCG.
19. application as claimed in claim 1 is characterized in that, FSH replaces with aromatase inhibitor or clomiphene citrate.
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| US20150273020A1 (en) * | 2007-05-11 | 2015-10-01 | Lori R. Bernstein | Hormone Normalization Therapy and Uses Therefor |
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| US4589402A (en) | 1984-07-26 | 1986-05-20 | Serono Laboratories, Inc. | Method of in vitro fertilization |
| US5705478A (en) * | 1989-02-21 | 1998-01-06 | Washington University | Covalently linked β subunits of the glycoprotein hormones as antagonists |
| WO1998058657A1 (en) | 1997-06-20 | 1998-12-30 | Akzo Nobel N.V. | Gonadotropin releasing hormone antagonist |
| ZA987497B (en) | 1997-09-08 | 1999-02-23 | Akzo Nobel Nv | Expression of gonadotropins in dictyostelium |
| US6090848A (en) * | 1997-12-01 | 2000-07-18 | Sigma-Tau Healthscience S.P.A. | Compositions and methods for increasing the concentration and/or motility of spermatozoa in humans |
| ATE317266T1 (en) | 1999-02-24 | 2006-02-15 | Novo Nordisk As | IN VITRO METHOD FOR SYNCHRONIZING OOCYTE MATURATION |
| BR0010709B1 (en) * | 1999-05-07 | 2011-11-29 | use of lh for the production of a drug to induce paucifoliculogenesis or unifoliculogenesis in anovulatory women. | |
| CZ302835B6 (en) | 2000-01-27 | 2011-11-30 | Laboratoires Serono Sa | Pharmaceutical composition |
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2002
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- 2002-09-12 JP JP2003526430A patent/JP2005501918A/en active Pending
- 2002-09-12 CN CNB028175735A patent/CN100536912C/en not_active Expired - Fee Related
- 2002-09-12 EP EP02758598A patent/EP1425032A2/en not_active Withdrawn
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Also Published As
| Publication number | Publication date |
|---|---|
| CN1553808A (en) | 2004-12-08 |
| PL369098A1 (en) | 2005-04-18 |
| MXPA04002256A (en) | 2004-07-23 |
| BR0212429A (en) | 2004-10-26 |
| MEP39208A (en) | 2011-02-10 |
| UA82650C2 (en) | 2008-05-12 |
| US7405197B2 (en) | 2008-07-29 |
| WO2003022302A3 (en) | 2003-12-18 |
| WO2003022302A2 (en) | 2003-03-20 |
| EA200400427A1 (en) | 2004-08-26 |
| CA2457849A1 (en) | 2003-03-20 |
| NO20040991L (en) | 2004-03-08 |
| IL160780A0 (en) | 2004-08-31 |
| ZA200400835B (en) | 2005-04-26 |
| RS21004A (en) | 2006-12-15 |
| HRP20040087A2 (en) | 2004-12-31 |
| EP1425032A2 (en) | 2004-06-09 |
| HK1067867A1 (en) | 2005-04-22 |
| KR20040032954A (en) | 2004-04-17 |
| JP2005501918A (en) | 2005-01-20 |
| AR036592A1 (en) | 2004-09-22 |
| EA009330B1 (en) | 2007-12-28 |
| US20050065069A1 (en) | 2005-03-24 |
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